1. Technical Field of the Invention
The invention concerns the preparation of cells or dispersed active substances into high-concentration microcapsules. Microcapsules having a shell and a core for receiving the cells or dispersed active substances are prepared by various processes.
2. Description of the Prior Art
In medicine, there is the need to introduce living cells into the living human body in the form of islands, which are supplied there with nutrients and produce and secrete hormones missing because of disease-related disorders. Diabetes mellitus is named as an example, where the cells that produce insulin are obtained in the form of the so-called islands of Langerhans and introduced into the liver or the pancreas. In order to suppress the immune reactions it is necessary to provide these cells with a shell in the form of a capsule, whose core they then form. A similar need for encapsulating exists for insoluble but dispersed active substances.
Processes for micro-encapsulation are known. It is observed that in the case of capsules with a sufficiently large diameter, i.e. of over 600 xcexcm, the reception of a core is possible without any problems. In contrast thereto, in the case of substantially smaller diameters, most of the capsules produced are without core, i.e empty. A further requirement results from the fact that the number of cells or pies of tissue to be introduced into the capsule as the core may not exceed a specific magnitude, as their inner regions would become necrotic due to deficient supply. In order to satisfy the body""s need for the hormones generated by the cells to a sufficient extent, the volume or quantity of the core material to be introduced is specified. In the case of a diabetes disease, in order to produce the necessary quantity of insulin, more or less one million islands of Langerhans have to be implanted. If one were to use cores with a large diameter, a volume would have to be administered that exceeds considerably physical tolerance. Moreover, the exact placement of the cells, which is desirable per se, would almost prove impossible because of the high own space requirements. A further disadvantage consists therein that, owing to the large diffusion paths between the shell and the core, additional supply problems can occur. Because of the aforementioned reasons, the use of capsules with a large diameter, i.e. of over 600 xcexcm, is ruled out in practice. The use of capsules with a small diameter does not offer a remedy in this respect, because the reduction of the original volume of a single capsule causes the proportion of the empty capsules, i.e. those not provided with a core, to increase significantly. In order to introduce the same quantity of cells or active substance, no tangible reduction in the total volume to be applied is obtained. In this case, a large proportion of empty and therefore medically inactive, but on the other hand non degradable material would be administered. In order to apply one million islands of Langerhans, an own volume of more or less 100 to 200 ml is necessary.
On this basis, it is the object of the invention to prepare cells or dispersed active substances into micro-encapsulated form, the proportion of microcapsules with cell and active substances being high while the own volume required is minimum.
In accordance with the invention, the task is solved herein that the air pressure or the diameter of the channels in the spray nozzle or the flow rate of the solution is set so that the droplet volume is 1.5 to 2 times the core volume. The microcapsules are then supplied to a density centrifugal separator with a density gradient adjusted so that he density of the used medium is higher than that of the empty microcapsules shells but lower than the density of the core-containing shells.
The central idea of the invention is, contrary to the aforementioned and known problems, to prepare capsules with a small diameter and then in a separation process to separate the empty and therefore biologically inactive capsules. Thus there is a concentration of the small core-containing capsules.
Capsules with a small diameter are prepared in that a spray nozzle provided with two channels is used, one channel, usually the outer one, being impinged by air, the inner one by a solution, which contains both the cells or the active substances as well as the shell material, i.e. the material for the capsule, in soluble form. The air flow causes droplets to break off at a specific size. The separating droplets reach a precipitation bath, where the shell is formed. By varying the air pressure correspondingly, selection of the diameter of the inner channel of the spray nozzle as well as the flow rate of the solution, droplets can be obtained whose volume comprises more or less 1.5 to 4 times the core volume. The core volume is specified by the staring material and the process used to obtain it. The shell surrounds the core directly and on all sides, without the retention of hollow volumes, so that the droplet size determines the volume of the capsule and, because of the defined, constant core volume, also the volume of the shell. The capsule diameter is a maximum of 200 xcexcm. Larger diameters have longer diffusion paths which result in a deficient supply. Then, the reaction products, containing a multitude of empty capsules, are supplied to a density centrifuge in which the density gradient is adjusted so that the density of the medium is higher than that of the shell material but lower than the density of the core-containing shell. Thus, empty capsules are separated from those with a core.